Multiple myeloma (“MM”) is an incurable malignancy arising from postgerminal mature B cells, characterized by an excess of monotypic plasma cells in the bone marrow and elevated levels of monoclonal immunoglobulins in the serum and/or urine (Lonial et al., 2012, J Clin Oncol 30:1953-1959). Common clinical sequelae include lytic bone lesions, fractures, myelosuppression, and renal failure. In the United States, the estimated annual diagnosed incidence is 20,000 (Lonial et al., 2012, J Clin Oncol 30:1953-1959). MM accounts for 15% of all hematologic malignancies and 2% of all malignancies (Lonial et al., 2012, J Clin Oncol 30:1953-1959). Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival (OS) and event-free disease periods in MM (Lonial et al., 2012, J Clin Oncol 30:1953-1959), although relapses are inevitable. Newer therapeutic agents, such as proteasome inhibitors (currently approved: Velcade® (bortezomib), Kyprolis® (carfilzomib)), and the immunomodulatory drugs thalidomide, Revlimid® (lenalidomide), and Pomalyst® (pomalidomide) have demonstrated clinical benefit in patients with newly diagnosed, relapsed or refractory disease (Lonial et al., 2012, J Clin Oncol 30:1953-1959). Despite these therapeutic advances, long-term control of relapsed or refractory MM remains an unmet medical need for most MM patients. Progressive disease that is resistant to both immunomodulatory drugs (IMiDs) and proteasome inhibitors is associated with a particularly poor prognosis (Lonial et al., 2012, J Clin Oncol 30:1953-1959). As such, there remains an important need for additional novel therapies to augment existing first-generation agents and continue to improve patient outcome.
CS1 (also known as SLAMF7, CRACC, 19A, APEX-1, and FOAP12) is a cell surface glycoprotein that has emerged as a new target antigen for therapeutic antibodies in multiple myeloma (MM) (Lonial et al., 2012, J Clin Oncol 30:1953-1959). Elotuzumab is a humanized monoclonal immunoglobulin G1 antibody targeting CS1 (see, e.g., PCT publications WO 2004/100898, WO 2005/102387, WO 2008/019376, and WO 2008/019378; see also U.S. Pat. Nos. 8,088,898, 8,133,981, 8,008,450, 8,445,646, 8,349,330, 8,461,306, 8,444,980, 8,436,146, 7,709,610, 8,632,772, and 7,842,293). Elotuzumab has shown encouraging antimyeloma activity in preclinical studies when used alone or in combination with other approved agents. For example, elotuzumab and lenalidomide have certain complementary mechanisms of action. Lenalidomide has been shown to increase the number and anti-MM cytotoxic activity of NK cells (Lonial et al., 2012, J Clin Oncol 30:1953-1959). Elotuzumab acts primarily through NK cell-mediated ADCC (Lonial et al., 2012, J Clin Oncol 30:1953-1959). A Phase III clinical trial, ELOQUENT-2, evaluated the efficacy and safety of elotuzumab in combination with lenalidomide and dexamethasone, as compared with lenalidomide and dexamethasone alone, in patients with relapsed or refractory multiple myeloma. In patients with relapsed or refractory multiple myeloma, the addition of elotuzumab to lenalidomide and dexamethasone, as compared with lenalidomide and dexamethasone as control therapy, improved progression-free survival and the overall response rate, showing that direct activation and engagement of the innate immune system selectively to target myeloma cells can provide clinically meaningful and statistically significant improvements in treatment outcomes. Specifically, Kaplan-Meier curves for progression-free survival showed early and increasing separation between the two groups over time. Patients receiving elotuzumab had a relative reduction of 30% in the risk of disease progression or death as compared with the control group (Lonial et al., 2015, N Engl J Med, 373:621-631).
Although the results with elotuzumab are promising, there remains a need to identify novel therapies that do not exert their anti-myeloma effect primarily via NK cell-mediated ADCC (Zonder, 2012, Blood, 120:552-559), in part because MM patients with advanced disease often have an impaired immune system (Pratt, 2007, Br J Haematol 138:563-579). Therapies that work effectively with an impaired immune system would be desirable.